110224-66-3Relevant academic research and scientific papers
Immobilization of malarial (Plasmodium falciparum) dihydrofolate reductase for the selection of tight-binding inhibitors from combinatorial library
Thongpanchang, Chawanee,Taweechai, Supannee,Kamchonwongpaisan, Sumalee,Yuthavong, Yongyuth,Thebtaranonth, Yodhathai
, p. 5006 - 5012 (2008/02/08)
A simple procedure for selection of tight-binding inhibitors of mutant dihydrofolate reductases from Plasmodium falciparum (PfDHFRs) based on preferential binding to the enzyme immobilized on a Sepharose column has been described. PfDHFRs with a cysteine residue at the C-terminal have been prepared in order to immobilize to a thiopropyl-Sepharose gel via S-S linkage. The amount of immobilized DHFRs was estimated to be 4-5 mg/g of dried gel, and the activities of bound DHFRs were comparable to that of free enzymes. The prepared immobilized enzyme has been used for the selection of tight-binding inhibitors from combinatorial libraries, based on the affinities of each ligand with the enzyme. Free ligands were then identified and analyzed quantitatively by high-performance liquid chromatography-mass spectrometry, and the components with high binding affinity of the library could thus be realized. Results could be confirmed by quantitative analysis of the bound ligands released from the enzyme by guanidine hydrochloride treatment.
2,4-Diamino-5-benzylpyrimidines as Antibacterial Agents. 8. The 3,4,5-Triethyl Isostere of Trimethoprim. A Study of Specificity
Roth, Barbara,Aig, Edward
, p. 1998 - 2004 (2007/10/02)
3,4,5-Triethylacetophenone was synthesized in 60percent yield by a Friedel-Crafts reaction from 4-ethylacetophenone and converted to 2,4-diamino-5-(3,4,5-triethylbenzyl)pyrimidine (2), a trimethoprim (1) isostere, by standard techniques.This compound is more lipophilic than 1 by three log units (log P, octanol/water).Compound 2 was approximately equipotent with 1 in inhibiting Escherichia coli dihydrofolate reductase (DHFR), 2-fold more potent against P. berghei and N. gonorrhoeae DHFR, and 10 and 25 times better an inhibitor of rat and chicken liver DHFR, respectively.Although the 3,4-dimethoxy analogue 19 was 10-fold less inhibitory to E. coli DHFR than 1, it was 3-4 times more potent on the vertebrate isozymes, whereas the diethyl congener 10 followed 19 in its E. coli DHFR binding but was less active on rat and chicken DHFR.Therefore, a significant portion of the selectivity of 1 for bacterial, as opposed to vertebrate, DHFR, involves the methoxy functions.An analysis of the X-ray data on 1 and 2 complexed with chicken DHFR, coupled with kinetic data, led to the conclusion that the differences in binding energies of the methoxy and ethyl compounds probably involve desolvation factors, as well as direct energies of interaction with protein atoms.Thus, one cannot invoke lipophilicity or shape alone in explaining the relationship in properties of 1 and 2.
